1. Field of the Invention
The invention relates to the manufacture of rapidly disintegrating, particulate active substance carriers. More specifically, it relates to a process for the manufacture of porous, active substance-containing pellets for peroral application based on chitosan or a basic chitosan derivative. Furthermore, it relates to chitosan pellets obtained from this process and their use for the manufacture of medicaments and diagnostic agents.
2. Description of the Related Art
Particulate active substance carriers enjoy great popularity in pharmaceutical technology. In products intended for peroral application, they have the advantage over liquid administration forms of being lighter and more compact, possessing greater chemical stability and enabling more accurate dosage. An advantage of multiparticulate preparations such as pellets over xe2x80x9csingle unitsxe2x80x9d such as tablets is the better reproducibility of their behaviour, above all when subjected to highly variable physiological conditions, since due to the large number of the administered pellets their overall behaviour develops according to statistical rules around an expected average value and the effect of individual outliers is not as great as can be the case in a tablet.
The state of the art knows a great number of carrier materials that are suitable for forming pellets. Basically, these are biocompatible substances with different chemical, physicochemical and mechanical properties. In the particular case, the selection depends on technical, economical and regulatory parameters, e.g., from the compatibility of the carrier material with the active agent(s), from the disintegration and dissolution properties, from th stability of the preparation, the raw material price, the processibility, the positive regulatory status for peroral application, etc.
Apart from pellets for preparations with controlled release of active substance, the state of the art also describes pellets with rapid-disintegration properties, which are capable of quickly releasing the active substance contained therein. Corresponding drug forms, also called acute forms, are particularly asked for in sporadically occurring indications where pharmacological action is to take place as quickly as possible. Examples are analgesics, antitussives, antiallergics, antiasthmatics, angina pectoris agents, and others. The carrier substances in such preparations are generally hydrophile or water-soluble in order to enable the desired disintegration properties. The latter are, however, also dependent on further parameters such as the presence of so-called disintegrants, i.e. substances capable of quickly absorbing water under intense swelling, or on an effective surface that is as large as possible.
Pellets having a large outer surface have a small particle size as a consequence. For a surface to be effective for the purpose of dissolution, it must be wettable, which can be ensured either by selecting the carrier material or by adding wetting agents. As an alternative, a large surface can also be due to great porosity. In that case, the particle diameter plays a rather subordinate part.
DE 42 01 172 C1 describes pellets which contain aloe vera extract as active substance and which contain gelatine or collagen as carrier, the gelatine preferably being of a cold water-soluble type.
A further carrier substance, e.g. dextrane, a sugar, sugar alcohol, glycine, or polyvinyl pyrrolidone, may also be contained. As a process of manufacture a dripping method is proposed, for instance employing the apparatus disclosed in DE 37 11 169 A1, wherein the pellets are produced by solidifying droplets in a cooling liquid, preferably in liquid nitrogen. Subsequent freeze-drying leads to the desired final product, which should possess high porosity and disintegration speed.
DE 42 01 173 A1 also discloses such pellets, but these contain a dihydropyridine derivative as active substance.
These gelatine-based cryopellets make use of the long-since known suitability of this carrier material for freeze drying to produce porous products: in Germany, for example, products of this kind for oral (e.g. Imodium(copyright) lingual, freeze-dried platelets or lamellae, by the firm of Janssen Cilag) and parenteral (e.g. Mumpsvax(copyright) dry substance) application are available on the market.
These gelatine-containing or collagen-containing preparations have the disadvantage that their success is being adversely affected by the insecurity of the population with regard to the danger of BSE contamination. Many patients or physicians prefer products without gelatine.
It is thus the object of the present invention to provide a process for the manufacture of porous, rapidly disintegrating pellets which does not require the use of gelatine, collagen or of derivatives thereof. A further object is to provide a gelatine- and collagen-free, porous, rapidly disintegrating pellets as active substance carrier for the manufacture of medicaments and diagnostic agents.
The object is achieved according to the present invention by a process for the manufacture of porous, rapidly disintegrating, active substance-containing pellets based on chitosan or a basic chitosan derivative according to a dripping method, characterized in that: a) an aqueous solution or dispersion is prepared wherein chitosan or the basic chitosan derivative, one or more active substances, an acid having a boiling point of maximally 140xc2x0 C., and possibly further auxiliary substances are present predominantly in solution; b) the aqueous solution or dispersion is dripped into a cooling liquid having a temperature of maximally xe2x88x925xc2x0 C. and is thereby solidified in the form of droplets; c) the solidified droplets or pellets are isolated; and d) dried, and the acid is removed from the pellets.